Stroke often involves the cerebral cortex and is a leading cause of functional disability affecting nearly 800,000 people per year in the United States. The collective negative personal, social and economic impacts of this disorder are staggering. One of the common clinical consequences of the most frequent form of stroke, namely middle cerebral artery infarction, is severe impairment of upper extremity motor function because of damage to the primary motor cortex (M1) and the adjacent parietal somatosensory cortex (S1). Although there appears to be considerable functional plasticity in the adult brain, the mechanisms underlying motor recovery following brain injury to both M1 and S1 remain poorly understood. Our major goal is to test the hypothesis that a central mechanism of functional recovery of hand and arm movement after M1 and S1 injury occurs through reorganization of axon connections from spared motor cortex to the brainstem and spinal cord as a result of forced use physical therapy. We expect that favorable motor recovery and enhanced axonal reorganization will be accompanied by upregulated neurotrophic molecular factors. We also plan to study how learned non-use affects these same molecular and connectional responses with the goal of pinpointing cellular mechanisms that can serve as targets for multimodal therapeutic interventions in moderate to severely impaired patients with cortical injury to M1 and S1 who do not respond to current therapies. We will study these molecular and axon remodeling responses from spared regions of the injured and uninjured hemisphere, because these brain regions represent highly accessible targets for non-invasive and invasive therapeutic intervention strategies in stroke patients. Neuroplastic responses of spared corticospinal and corticobulbar projections will be correlated with neurotrophic factor signaling and recovery of arm and hand movements using multiple, state-of-the art anatomical, molecular and behavioral methodologies. This project will lead to a greater understanding of the contribution of spared axonal projection systems and corresponding neurotrophin gene regulation profiles in both hemispheres to recovery of arm and hand movement following forced-use therapy and advanced learned non-use. This information will also assist in identifying cortical targets that may serve as important internal resources for the application of creative, non-invasive and invasive therapies to enhance motor recovery after common lateral cortical injury.